MOTS-c (Mitochondrial Open Reading Frame of the 12S
rRNA-c)

2000-2014

The Mitochondrial Mystery

More Than Just Power Plants

Scientists had long studied mitochondria as cellular power plants — organelles that convert food into ATP, the energy currency of cells. But mitochondria have their own DNA (mtDNA), inherited only from mothers. Could this ancient DNA do more than just encode energy machinery?

Pinchas Cohen's laboratory at USC began exploring this question. In 2013, they discovered humanin — a small peptide encoded in mtDNA that had protective effects throughout the body. Mitochondria, it seemed, could produce hormones.

This raised a tantalizing possibility: were there other mitochondrial peptides? And could they explain some of the mysterious connections between metabolism, exercise, and aging?

2015

The Discovery

Finding MOTS-c

In 2015, Cohen's team announced the discovery of MOTS-c (Mitochondrial Open Reading Frame of the 12S rRNA-c). This 16-amino-acid peptide was encoded in a region of mitochondrial DNA previously thought to be non-coding.

MOTS-c had remarkable effects. When given to mice on high-fat diets, it prevented weight gain and insulin resistance. It improved glucose metabolism and enhanced cellular energy efficiency. The peptide seemed to recreate some of exercise's metabolic benefits.

The finding was revolutionary. Mitochondria — organelles that had been part of our cells for over a billion years — were sending signals that could regulate whole-body metabolism.

2015-2020

The Exercise Connection

Running Releases MOTS-c

Researchers made a key observation: exercise increased MOTS-c levels. When people exercised, MOTS-c rose in their muscles and bloodstream. This suggested MOTS-c might be one of the molecular signals mediating exercise benefits.

Further studies showed MOTS-c levels declined with age. Old mice had less MOTS-c than young mice. Old humans had less than young humans. Could declining MOTS-c contribute to age-related metabolic dysfunction?

When researchers gave MOTS-c to old mice, they became metabolically younger. They ran farther, handled glucose better, and showed improved muscle function. MOTS-c was living up to its nickname: 'the exercise mimetic.'

2020-2023

Mechanism and Muscle

How MOTS-c Works

Scientists began unraveling MOTS-c's mechanism. The peptide activated AMPK — the same metabolic master switch triggered by exercise and caloric restriction. It improved mitochondrial function, enhanced fat burning, and promoted glucose uptake into muscles.

In 2021, a landmark study showed MOTS-c could restore youthful running capacity to old mice. Aged mice given MOTS-c doubled their running endurance and maintained healthy muscle tissue that typically deteriorates with age.

The implications were profound. A peptide produced by mitochondria could potentially treat age-related metabolic disease, diabetes, and physical frailty — three of the biggest challenges of aging societies.

2023-Present

Toward Human Applications

From Mice to Medicine

MOTS-c is now being prepared for human studies. Researchers are developing stable formulations and determining optimal dosing strategies. The goal is to test whether the dramatic benefits seen in mice translate to humans.

Potential applications are broad: type 2 diabetes, obesity, age-related sarcopenia (muscle loss), metabolic syndrome. For people who can't exercise due to disability or illness, MOTS-c might provide some of exercise's benefits.

The discovery has also transformed how we think about mitochondria. These ancient organelles aren't just energy producers — they're metabolic communicators that help coordinate our body's response to exercise, stress, and aging.